Abstract
Simple SummaryHypoxia is a common feature of solid tumors and associated with poor outcome in most cancer types and treatment modalities, including radiotherapy, chemotherapy, surgery and, most likely, immunotherapy. Emerging strategies, such as proton therapy and combination therapies with radiation and hypoxia targeted drugs, provide new opportunities to overcome the hypoxia barrier and improve therapeutic outcome. Hypoxia is heterogeneously distributed both between and within tumors and shows large variations across patients not only in prevalence, but importantly, also in level. To best exploit the emerging strategies, a better understanding of how individual hypoxia levels from mild to severe affect tumor biology is vital. Here, we discuss our current knowledge on this topic and how we should proceed to gain more insight into the field.Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier in cancer treatment. The distribution of hypoxia levels is highly heterogeneous, ranging from mild, almost non-hypoxic, to severe and anoxic levels. The individual hypoxia levels induce a variety of biological responses that impair the treatment effect. A stronger focus on hypoxia levels rather than the absence or presence of hypoxia in our investigations will help development of improved strategies to treat patients with hypoxic tumors. Current knowledge on how hypoxia levels are sensed by cancer cells and mediate cellular responses that promote treatment resistance is comprehensive. Recently, it has become evident that hypoxia also has an important, more unexplored role in the interaction between cancer cells, stroma and immune cells, influencing the composition and structure of the tumor microenvironment. Establishment of how such processes depend on the hypoxia level requires more advanced tumor models and methodology. In this review, we describe promising model systems and tools for investigations of hypoxia levels in tumors. We further present current knowledge and emerging research on cellular responses to individual levels, and discuss their impact in novel therapeutic approaches to overcome the hypoxia barrier.
Highlights
Solid tumors generally show regions with insufficient oxygen supply, defining them as hypoxic [1]
The significance of various hypoxia levels for cancer treatment is well demonstrated by the higher cell kill of sparsely ionizing radiation in the presence of oxygen compared to under anoxic conditions, where a steep decrease in radiosensitivity is seen when the level changes from mild hypoxia of about 2% O2 to severe hypoxia of below 0.02% O2 (Figure 1C) [3]
Detailed understanding of hypoxia sensing and responses of cancer cells grown at different oxygen concentrations has been obtained, but our knowledge of how hypoxia levels influence the cellular interactions within the tumor microenvironment is scarce (Figure 5)
Summary
Solid tumors generally show regions with insufficient oxygen supply, defining them as hypoxic [1]. Individual hypoxia levels induce biological responses, like cancer cell survival and metastasis, that impair the treatment effect [4], and there is a large difference in the hypoxia level most strongly associated with poor radiotherapy outcome within and across cancer types (Figure 1C) [5]. This knowledge documents the importance of incorporating hypoxia levels in the work to understand treatment resistance mechanisms and implement new, upcoming therapeutic approaches, like immunotherapy, and radiation therapy with particles or in combination with hypoxia targeting drugs. We further review current knowledge of biological responses in cancer cells and the tumor microenvironment to individual hypoxia levels, and discuss possible implications of hypoxia levels for the success of new therapeutic approaches
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